Abstract:The revival of the old and, for several years, abandoned era of suppressor T cells came in the 1990s with two works that resurrected the idea of CD8 + suppressor T cells [1,2]. The revival was further strengthened when a subset of CD4 + T cells constitutively expressing high levels of the IL-2R α-chain (CD25) and possessing suppressor activity was identified [3]. These cells, termed regulatory T (Treg) cells, were able to prevent disease in various models of autoimmunity, and to suppress transplant rejection a… Show more
“…IFN promoted Th1 polarization at the expense of peripheral Treg induction, a data indicating that, during inflammation, IFN may subvert microenvironmental networks normally promoting tolerance maintenance, as in the gut. In addition, the finding that type-I IFNs are also potent inducers of PD-L1 on a variety of cells including Treg is consistent with the evidence showing that the PD-1 is overexpressed by activated Treg and, upon PD-L1 interaction, negatively regulates the expansion and suppressive function of activated Treg by controlling STAT-5 phosphorylation, at the site of inflammation in chronic HCV infection [15,26]. Such a mechanism (contra-suppression?)…”
“…IFN promoted Th1 polarization at the expense of peripheral Treg induction, a data indicating that, during inflammation, IFN may subvert microenvironmental networks normally promoting tolerance maintenance, as in the gut. In addition, the finding that type-I IFNs are also potent inducers of PD-L1 on a variety of cells including Treg is consistent with the evidence showing that the PD-1 is overexpressed by activated Treg and, upon PD-L1 interaction, negatively regulates the expansion and suppressive function of activated Treg by controlling STAT-5 phosphorylation, at the site of inflammation in chronic HCV infection [15,26]. Such a mechanism (contra-suppression?)…”
“…Natural Treg cells are completely demethylated within the foxp3‐TSDR , whereas murine induced Treg cells may either exhibit a methylated foxp3‐TSDR or differentiate into fully stable Treg cells with a demethylated foxp3‐TSDR under particular conditions, e.g. by antigen‐specific signals through tolerogenic DEC205 vaccination . Hence, this methylation is a valid marker characterizing stable committed Treg cells regardless of the Treg cell type (natural or induced) …”
Treg cells are stable and exhibit unmethylated foxp3-TSDR, and that both Treg populations are functionally suppressive in healthy and septic mice. DEREG mice depleted of Foxp3 + Treg cells exhibit higher disease scores, mortality rates and interleukin-6 expression levels than do non-depleted DEREG mice in early-phase sepsis, a finding indicating that Foxp3 + Treg cells limit the hyper-inflammatory response and accelerate recovery. Treg cell depletion before secondary infection with P. aeruginosa 1 week after caecal ligation and puncture does not influence cytokine levels or the course of secondary infection. However, a moderate Treg cell recurrence, which we observed in DEREG mice during secondary infection, may interfere with these results. In summary, Treg cells contribute to a positive outcome after early-phase sepsis, but the data do not support a significant role of Treg cells in immune paralysis during late-phase sepsis.
“…PD‐1, considered as an inhibitory receptor delivering negative signals to conventional T cells (Tconvs), sustains development, maintenance, and suppressive function of peripherally induced Tregs upon engagement with its own ligand (PD‐L1) . On the other side, PD‐1 tempers expansion and function of already established Tregs . Contrary to PD‐1, OX40 is considered as a costimulatory molecule conveying prosurvival signals to Tconvs .…”
Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T‐bethighIFN‐γ– “T‐helper (Th)1‐suppressing” phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon‐gamma (IFN‐γ; T‐bet+IFN‐γ+), thus becoming “Th1‐like” cells. OX40‐expressing and Th1‐suppressing Tregs were enriched in the Helios‐positive subset, carrying highly demethylated Treg cell‐specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2‐like monocytes and macrophages, boosted OX40+ Treg proliferation and antagonized the differentiation of Th1‐like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin‐12 and IFN‐γ, ultimately leading to complete, full Th1‐like Treg differentiation. Conclusion: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ. (Hepatology 2014;60:1494–1507)
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